In the United States, 213,000 new cases of lung cancer are diagnosed yearly; 60% of these patients die within one year. Due to the heterogeneity of lung cancer, personalized therapies tailored to the molecular signatures of a tumor are anticipated to provide better clinical efficacy. To make widespread use of personalized therapies a reality, clinicians must have the ability to rapidly classify the tumor signature, identify treatments effective in that tumor subtype, deliver therapeutics effectively to the tumor, and monitor the tumor signature during the course of treatment. Tumor targeting ligands are becoming an important component in the development of customized therapies. The long-term objective of my laboratory is to develop comprehensive panels of tumor-specific ligands for functional diagnosis and targeted therapy for lung cancer, including lung cancer arising in never smokers. For this purpose, my laboratory has biopanned phage-displayed peptide libraries on a series of human non small cell lung cancer (NSCLC) cell lines. From these selections, 11 novel peptidic ligands were isolated. The peptides bind selectively to NSCLC cells while avoiding nonmalignant bronchial epithelial cells, and display cell binding affinities i the picomolar to low nanomolar range. Peptide binding was determined on 40 different human NSCLC cell lines; 80% of the cell lines tested bind to at least one peptide and > 35% bind 2 or more of the ligands. Thus, this panel of peptides may cover a large fraction of NSCLC cases encountered in the clinic. These peptides have the added benefit that they trigger cellular uptake allowing for therapeutics to be delivered intracellularly. Lastly, the peptides home to tumors in animal models. These ligands are primed to be translated into effective delivery systems for the treatment of NSCLC. The objective of this project is to fully optimize these delivery reagents for molecularly targeted drug delivery. Aim 1 will determine the breadth and specificity of peptide binding to uncultured primary human NSCLC tumor samples. In Aim 2, unique multivalent peptide-guided stealth liposomes will be synthesized and optimized to achieve the highest level of liposome delivery to the tumor while minimizing uptake in other tissues and clearance by the reticuloendothelial system (RES). The role of peptide valency, affinity, peptide charge, and peptide density will be assessed in a systematic fashion. Finally, in Aim 3, the anti-tumor efficacy of drug loaded liposomes developed in aim 2 will be assessed in animal xenograft models of NSCLC. An innovative nanoliposome formulation will be employed to achieve high load loading and tune the drug release kinetics. Compartmental pharmacokinetic (PK) and pharmacodynamic (PD) studies will be executed. Upon completion, a validated suite of NSCLC tumor targeting agents will have been generated. The molecularly-targeted delivery systems developed will dramatically improve efficacy of NSCLC treatment. PUBLIC HEALTH RELEVANCE: In the United States, ~157,000 people will die of lung cancer this year; development of effective treatments for lung cancer is of critical importance for patients and society as a whole. The proposed research will result in a validated suite of tumor targeting agents that can be employed to deliver chemotherapeutics specifically to tumors while avoiding normal tissues. The molecularly-targeted delivery systems developed will dramatically improve efficacy of lung cancer treatment.